Phosphonic acid compounds

ABSTRACT

Compound of formula (I):   &lt;IMAGE&gt; (I)  in which: R1 represents a hydroxyl, alkoxy or amino (unsubstituted or substituted) group, R2 represents an unsubstituted or substituted alkyl group, X1 represents -NH-, X2 represents -0-, R3 represents a hydrogen atom or an alkyl or phenyl group, R4 represents an alkyl group which is always substituted with one or more hydroxyl, benzyloxy, benzyloxycarbonylamino, amino, mono- or dialkylamino, acetoxy or 2,2-dimethyl-1,3-dioxolan-4-yl groups, such groups being identical or different, R5 represents a 3-indolylmethyl, naphthylmethyl, alkyl, phenyl or benzyl group, its isomers as well as its addition salts with a pharmaceutically acceptable acid or base, and medicinal products containing the same are useful as endothelin convertase inhibitor.

The present invention relates to new phosphonic acid compounds.

Endothelins are peptides of 21 amino acids having very potentvasoconstrictor activity. These endothelins are synthesized from aprecursor, big endothelin, by an enzyme known as "endothelin convertingenzyme" or proendothelin convertase. This enzyme belongs to themetalloprotease class, and it may be inhibited by phosphoramidon. Anincrease in plasma endothelin levels has been demonstrated in disorderssuch as hypertension, angina, myocardial infarction, renalinsufficiency, shock, diabetes, hypercholesterolemia, cerebralvasospasm, Raynaud's disease, inflammatory arthritis, cardiacinsufficiency and pulmonary hypertension. It has hence been postulatedthat endothelin might play a part in peripheral and myocardial ischemia,hypertension, renal insufficiency, hypoxic pulmonary vasoconstriction,asthma, atherosclerosis and arthritis. It was hence of special interestto synthesize substances that inhibit proendothelin convertase.

The prior state of the art is illustrated, in particular, by PatentsEP0,518,299 and WO 92/01,468.

The invention relates more especially to the compounds of formula (I):##STR2## in which: R₁ represents a hydroxyl or linear or branched (C₁-C₆) alkoxy group or an amino group (unsubstituted or substituted with 1or 2 linear or branched (C₁ -C₆) alkyl groups), R₂ represents a linearor branched (C₁ -C₆) alkyl group, unsubstituted or substituted with aphenyl or (C₃ -C₇) cycloalkyl group,

X₁ represents --NH--,

X₂ represents --O--,

R₃ represents a hydrogen atom, a linear or branched (C₁ -C₆) alkyl groupor a phenyl group,

R₄ represents a linear or branched (C₁ -C₆) alkyl group which is alwayssubstituted with one or more hydroxyl, benzyloxy,benzyloxycarbonylamino, amino, linear or branched (C₁ -C₆) mono- ordialkylamino, acetoxy or 2,2-dimethyl-1,3-dioxolan-4-yl groups, suchgroups being identical or different,

R₅ represents a 3-indolylmethyl, naphthylmethyl or linear or branched(C₁ -C₆) alkyl group or a phenyl or benzyl group,

their enantiomers, diastereoisomers and epimers as well as theiraddition salts with a pharmaceutically acceptable acid or base.

Among pharmaceutically acceptable bases, there may be mentioned, withoutimplied limitation, sodium hydroxide, potassium hydroxide, lithiumhydroxide, triethylamine, tert-butylamine, and the like.

Among pharmaceutically acceptable acids, there may be mentioned, withoutimplied limitation, hydrochloric, sulfuric, tartaric, maleic, fumaric,methanesulfonic, camphoric, and the like, acids.

The invention also encompasses the process for preparing the compoundsof formula (I), wherein the amino acid of the formula (II), in racemicform or the form of a pure enantiomer: ##STR3## in which: R'₁ representsa linear or branched (C₁ -C₆) alkoxy group or an amino group(unsubstituted or substituted with 1 or 2 linear or branched (C₁ -C₆)alkyl groups), and

R₅ has the same meaning as in the formula (I), is used as startingmaterial,

which compound is reacted with a compound of formula (III), in racemicform or the form of a pure enantiomer: ##STR4## in which R₂ and X ₁ havethe same meaning as in the formula (I) and P represents a suitableprotective group,

to yield a compound of formula (IV), the isomers of which, whereappropriate, are separated according to a standard separating technique:##STR5## in which R'₁, R₂, X₁, R₅ and P have the same meaning as above,

which is deprotected, depending on the nature of P, by a suitabletechnique, to yield the compound of formula (V): ##STR6## in which R'₁,R₂, R₅ and X₁ have the same meaning as above, which is reacted:

in an inert medium, at room temperature, with a chloroform solutionprepared beforehand by stirring the following in an inert medium:

one equivalent of a phenyl dichlorophosphate of formula (VII): ##STR7##one equivalent of the compound of formula (VIII):

    R'.sub.4 --X.sub.2 --H                                     (VIII)

in which

X₂ has the same meaning as in the formula (I),

R'₄ represents an alkyl group (substituted with one or more benzyloxy,benzyloxycarbonylamino, acetoxy or linear or branched (C₁ -C₆)dialkylamino or 2,2-dimethyl-1,3-dioxolan-4-yl groups),

and two equivalents of triethylamine,

to yield, after deprotection in a basic medium, the compound of formula(I/a), a special case of the compounds of formula (I): ##STR8## in whichR'₁, R₂, R₅ and X₂ have the same meaning as above and R"₄ represents analkyl group (substituted with one or more hydroxyl, benzyloxy,benzyloxycarbonylamino, acetoxy or linear or branched (C₁ -C₆)dialkylamino or 2,2-dimethyl-1,3-dioxolan-4-yl groups),

in which compound of formula (I/a) the group R"₄ may be converted, whenthe latter represents:

an alkyl group substituted with one or more benzyloxy groups, to analkyl group substituted with one or more hydroxyl groups, by catalytichydrogenation,

an alkyl group substituted with one or more acetoxy groups, to an alkylgroup substituted with one or more hydroxyl groups, by reaction withlithium hydroxide or sodium hydroxide,

which compound of formula (I/a):

may be subjected to conversion of the group R'₁ therein when the latterrepresents an alkoxy group to a corresponding hydroxyl group,

may be purified according to standard purification techniques,

may be subjected to separation of its isomers according to standardseparating techniques,

and may be convened to a corresponding salt of an acid or base.

The process for preparing the compounds of formula (I) also encompassesthe synthesis of the reference compound, phosphoramidon of formula:##STR9## Phosphoramidon was hitherto isolated from strains ofStreptomyces tanashiensis (Tet. Lett. 43, 97-100, 1972).

The subject of the present invention is also pharmaceutical compositionscontaining as active principle at least one compound of general formula(I) or one of its addition salts with a pharmacologcally acceptableacid, alone or in combination with one or more nontoxic, inertexcipients or vehicles.

Among the pharmaceutical compositions according to the invention, theremay be mentioned more especially those which are suitable for oral,parenteral or nasal administration, simple or sugar-coated tablets,sublingual tablets, hard gelatin capsules, troches, suppositories,creams, ointments, skin gels, and the like.

The dosage varies according to the patient's age and weight and thenature and severity of the complaint, as well as the administrationroute.

The latter may be oral, nasal, rectal or parenteral. Generally speaking,the unit dosage ranges between 0.1 and 1,000 mg for a treatmentadministered in 1 to 3 doses per 24 hours.

The examples which follow illustrate the invention but in no way limitit. The starting materials used in the examples are known startingmaterials or are prepared according to known procedures.

The abbreviations used in the examples are as follows:

Leu in place of the leucine residue

Trp in place of the tryptophan residue

Et in place of ethyl

Val in place of the valine residue

Ile in place of the isoleucine residue

cyclohexylAla in place of the cyclohexylalanine residue

tert-butylGly in place of the tert-butylglycine residue

Phe in place of the phenylalanine residue

Nal in place of the 2-naphthylalanine residue

Example 1 N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OHdisodium salt

Stage A: N-[(2,3-Diacetoxypropoxy)phenoxyphosphinyl]-(S)Leu-(S)Trp-OEt

4.8 mmol of 2,3-diacetoxypropanol dissolved in anhydrous chloroform areadded at 0°-5° C. to a mixture containing 4.8 mmol of phenyldichlorophosphate and 9.6 mmol of triethylamine in anhydrous chloroform.The resulting mixture is stirred for 3 hours at room temperature. Asolution containing 4.8 mmol of (S)Leu-(S)Trp-OEt in anhydrouschloroform (prepared by peptide coupling, according to the techniquedescribed by W. KONIG and R. GEIGER (Ber, 103, 788, 1970) of Z-Leu-OHand H-Trp-OEt) is then added to the above mixture. After 48 hours ofstirring at room temperature, the reaction mixture is washed with waterand then with saturated sodium chloride solution, dried, filtered andevaporated under vacuum. The oil obtained is purified by chromatographyon a silica column using a dichloromethane/ethyl acetate (70:30)mixture, and yields the expected product.

Stage B: N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OHdisodium salt

The product obtained in Stage A is saponified in a mixture containing1.75 ml of 1N sodium hydroxide and 20 ml of ethanol cooled to 0°-5° C.After evaporation of the ethanol, the residual oil is diluted withwater, washed several times with dichloromethane and then lyophilized.The lyophilizate is purified by passage through a SEPHADEX (LH-20)column. The combined aqueous phases are lyophilized again.

Yield: 50%

Mass spectrum: FAB: [M+Na]⁺ : m/z=538

EXAMPLE 2 N-[(2-Benzyloxyethoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OHdisodium salt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by2-benzyloxyethanol. Mass spectrum: FAB: [M+H]⁺ : m/z=576

Example 3 N-[(2-Hydroxyethoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OEtdisodium salt

The expected product is obtained by catalytic hydrogenation of 2.7 mmolof the compound obtained in Stage A of Example 2, at atmosphericpressure and at room temperature, in the presence of 50 ml of ethanol,230 mg of sodium bicarbonate and 6 ml of water and of a (50:50) PtO₂--Pd/C₁₀ % mixture as catalysts. After 48 hours of hydrogenation, thecatalysts are filtered off and the solution is evaporated. The residualoil is taken up with water, washed with dichloromethane and lyophilized.The lyophilizate is then dissolved in water, purified on a SEPHADEX(LH-20) column and then lyophilized again, and yields the expectedproduct.

Mass spectrum: FAB: [M+H]⁺ : m/z=492

EXAMPLE 4 N-[(2-Hydroxyethoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OHdisodium salt

The expected product is obtained by catalytic hydrogenation of thecompound described in Example 2 using the method described in Example 3.

Mass Spectrum: FAB: [M+H]⁺ : m/z=486

EXAMPLE 5 N-[(3-Hydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by3-acetoxypropanol and by saponification using lithium hydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=468

EXAMPLE 6N-[[2-(Benzyloxycarbonylamino)ethoxy]hydroxyphosphinyl]-(S)Leu-(S)Trp-OEtdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by2-(benzyloxycarbonylamino)ethanol. The saponification is carried outusing lithium hydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=609

EXAMPLE 7 N-{[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]hydroxyphosphinyl}-(S)Leu-(S)Trp-OEt, sodium salt

State A:N-{[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]phenoxyphosphinyl}-(S)Leu-(S)Trp-OEt

The expected product is obtained according to the process described inStage A of Example 1 by replacing 2,3-diacetoxypropanol by2,2-dimethyl-1,3-dioxolane-4- m-ethanol.

Stage B:N-{[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]hydroxyphosphinyl}-(S)Leu-(S)Trp-OEtsodium salt

A solution containing 63 mmol of sodium bicarbonate in 5 ml of water isadded to a solution containing 63 mmol of the compound obtained in thepreceding stage in 30 ml of ethanol. The medium is hydrogenated for 48hours at room temperature in the presence of platinum oxide as catalystunder a pressure of 1,200 mbar. After the catalyst has been filtered offand the solvent evaporated off, the residue is taken up with 50 ml ofwater. After the aqueous phase has been washed with ethyl acetate andfiltered, the expected product is obtained after lyophilization.

Mass spectrum: FAB: [M+H]⁺ : m/z=562

Infrared (Nujol):

δ_(co) ester=1728 cm⁻¹

δ_(co) amides=1653 cm⁻¹

EXAMPLE 8N-{[(1-Hydroxymethyl-2-hydroxy)ethoxy]hydroxy-phosphinyl]-(S)Leu-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 5 by replacing 3-acetoxypropanol in Stage A by1,3-diacetoxy-2-propanol.

Mass spectrum: FAB: [M+H]⁺ : m/z=484

EXAMPLE 9 N-[(3-Aminopropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OEtlithium salt

Stages A and B:N-{[(3-Benzyloxycarbonylamino)propoxy]hydroxy-phosphinyl}-(S)Leu-(S)Trp-OEtlithium salt

The expected product is obtained according to the process described inExample 6 by replacing benzyloxycarbonylamino)ethanol in Stage A by(benzyloxycarbonylamino)propanol.

Stage C: N-[(3-Aminopropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OEt lithiumsalt

The expected product is obtained after catalytic hydrogenation of thecompound described in the preceding stage using palladium/charcoal ascatalyst, at room temperature, at a pressure of 1,200 mbar, followed bylyophilization.

Mass spectrum: FAB: [M+2H-Li]⁺ : m/z=483

Example 10N-[((R)-2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by the isomer(R)-2,3-diacetoxypropanol and by saponification using lithium hydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=484

EXAMPLE 11N-[((S)-2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by the isomer(S)-2,3-diacetoxypropanol and by saponification using lithium hydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=484

EXAMPLE 12 N-[(3,4-Dihydroxybutoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by3,4-diacetoxybutanol and by saponification using lithium hydroxide.

Mass Spectrum: FAB: [M+H]⁺ : m/z=498

EXAMPLE 13 N-(1-Hydroxymethyl-3-hydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OH dilithium salt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by1-acetoxymethyl-3-acetoxypropanol and by saponification using lithiumhydroxide.

Mass Spectrum: FAB: [M+H]⁺ : m/z=498

EXAMPLE 14 N-(2,4-Hydroxybutoxy)hydroxyphosphinyl-(S)Leu-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by2,4-diacetoxybutanol and by saponification using lithium hydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=498

Example 15N-[(2,3,4-Trihydroxybutoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OH dilithiumsalt

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by2,3,4-triacetoxybutanol and by saponification using lithium hydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=514

EXAMPLE 16 N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Trp-OEtsodium salt

The expected product is obtained according to the process described inExample 7 using 2,3-diacetoxypropanol in Stage A.

Example 17 N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Val-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing (S)Leu-(S)Trp-OEt in Stage A by (S)Val-(S)Trp-OEtand by saponification using lithium hydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z =470

EXAMPLE 18: N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Ile-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing (S)Leu-(S)Trp-OEt in Stage A by (S)Ile-(S)Trp-OEtand by saponification using lithium hydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=484

Example 19:N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)cyclohexylAla-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing (S)Leu-(S)Trp-OEt in Stage A by(S)cyclohexylAla-(S)Trp-OEt and by saponification using lithiumhydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=524

EXAMPLE 20N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)tert-butylGly-(S)Trp-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing (S)Leu-(S)Trp-OEt in Stage A by(S)tert-butylGly-(S)Trp-OEt and by saponification using lithiumhydroxide.

Mass spectrum: FAB: [M+H]⁺ : m/z=484

EXAMPLE 21N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)tert-butylGly-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing (S)Leu-(S)Trp-OEt in Stage A by(S)Leu-(S)tert-butylGly-OEt and by saponification using lithiumhydroxide.

Mass Spectrum: FAB: [M+H]⁺ : m/z=411

Example 22 N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Phe-OHdilithium salt

The expected product is obtained according to the process described inExample 1 by replacing (S)Leu-(S)Trp-OEt in Stage A by (S)Leu-(S)Phe-OEtand by saponification using lithium hydroxide.

Mass Spectrum: FAB: [M+H]⁺ : m/z=445

EXAMPLE 23 N-[(2,3-Dihydroxypropoxy)hydroxyphosphinyl]-(S)Leu-(S)Nal-OEtsodium salt

The expected product is obtained according to the process described inExample 1 by replacing (S)Leu-(S)Trp-OEt in Stage A by (S)Leu-(S)Nal-OEtand by saponification using lithium hydroxide.

Mass Spectrum: FAB: [M+H]⁺ : m/z=495

EXAMPLE 24 Phosphoramidon disodium salt (N-[α-(S)-(rhamnopyranosyloxy)hydroxyphosphinyl]-(S)leu-(S)Trp-OH disodium salt)

The expected product is obtained according to the process described inExample 1 by replacing 2,3-diacetoxypropanol in Stage A by rhamnosetriacetate. The isomers obtained are then separated and purified bychromatography on a reversed-phase silica column (C₁₈) using water aseluent. The expected product possesses the same physicochemicalproperties as that of commercial phosphoramidon.

Mass Spectrum: FAB: [M+H]⁺ : m/z=588

Optical rotation: α_(D) ²⁰ =-30.1 (c=0.96%, water)

Pharmacological Study Of The Compounds Of The Invention EXAMPLE 25

In vivo study of the compounds of the invention on pithed rats

Sprague-Dawley rats (300-400 g) are anesthetized with ether. The animalsare then pithed and placed under artificial respiration. The vagusnerves are sectioned and the carotid arteries ligated. A catheter isintroduced into one of the carotid arteries to measure arterial bloodpressure. A second catheter is introduced into the vein of the penis toenable substances to be injected.

After a stabilization period, the animals receive an injection ofendothelin-1 (ET-1; 0.5 nmol/kg) or its precursor, b are recorded and,after the pressure has returned to its initial value (1 h 30 min to 2hours), a second injection of ET-1 or of big ET-1 is given in thepresence or absence of an infusion of a product of the invention or ofthe reference substance, phosphoramidon. Phosphoramidon and the productsof the invention had no effect on ET-1-induced hypertension. Incontrast, they inhibited big ET-1-induced pressor responses in adose-dependent manner, indicating an inhibition of ECE.

The results for IC₅₀ values of these substances with respect to big ET-1are collated below.

    ______________________________________                                        Example        IC.sub.50  (μg/kg/min)                                      ______________________________________                                        1              100                                                            3              280                                                            4              430                                                            8              480                                                            9              200                                                            10             230                                                            11             100                                                            12             140                                                            Phosphoramidon 125                                                            ______________________________________                                         Example 26

In vitro study of the compounds of the invention on perfused isolatedrat kidney

The studies are performed on kidneys prepared from male Wistar rats(300-400 g). The rats are anesthetized with pentobarbitone sodium (50mg/kg i.p.) and the left kidney is prepared so as to permit perfusionwith Tyrode solution. The variations in perfusion pressure are measuredcontinuously. The perfusion flow rate is 6 ml/min. After stabilization,a bolus injection of ET-1 (0.03 nmol) or of big ET-1 (0.4 nmol) isperformed and the pressor response is recorded. After the pressure hasreturned to the baseline value, a second injection of ET-1 or of bigET-1 is carried out, either in a control solution, or in the presence ofphosphoramidon or one of the products of the invention. None of theproducts had an effect on the pressor responses to ET-1. In contrast,phosphoramidon and the compounds of the invention substantiallyinhibited the pressor responses obtained with big ET-1. The IC₅₀ valuesof the products are calculated and the results are given in μM.

    ______________________________________                                        Example         IC.sub.50  (μM)                                            ______________________________________                                        1               4                                                             3               5                                                             4               7                                                             Phosphoramidon  0.9                                                           ______________________________________                                    

Example 27

Pharmaceutical composition

Composition formula for 1,000 tablets containing a 10 mg dose

    ______________________________________                                        Compound of Example 1    10 g                                                 Hydroxypropylcellulose   2 g                                                  Wheat starch             10 g                                                 Lactose                  100 g                                                Magnesium stearate       3 g                                                  Talc                     3 g                                                  ______________________________________                                    

We claim:
 1. A compound of formula (I): ##STR10## in which: R₁represents hydroxyl, linear or branched (C₁ -C₆) alkoxy or amino, whichis (unsubstituted or substituted with 1 or 2 linear or branched (C₁ -C₆)alkyl,R₂ represents linear or branched (C₁ -C₆) alkyl, unsubstituted orsubstituted with phenyl or (C₃ -C₇) cycloalkyl, X₁ represents --NH--, X₂represents --0--, R₃ represents hydrogen, linear or branched (C₁ C₆)alkyl or phenyl, R₄ represents linear or branched (C_(1-C) ₆) alkylwhich is substituted with one or more hydroxyl, benzyloxy,benzyloxycarbonylamino, amino, linear or branched (C₁ -C₆) mono- ordialkylamino, acetoxy, or 2,2-dimethyl-1,3-dioxolan-4-yl, such groupsbeing identical or different, R₅ represents 3-indolylmethyl,naphthylmethyl, linear or branched (C₁ -C₆) alkyl, phenyl, or benzyl,itsenantiomers, diastereoisomers and epimers as well as its addition saltswith a pharmaceutically-acceptable acid or base.
 2. A compound of claim1, wherein R₄ represents (C₁ -C₆) alkyl which is substituted with one ormore hydroxyl, its enantiomers, diastereoisomers and epimers as well asits addition salts with a pharmaceutically-acceptable acid or base.
 3. Acompound of claim 1, wherein R₅ represents 3-indolylmethyl, itsenantiomers, diastereoisomers and epimers as well as its addition saltswith a pharmaceutically-acceptable acid or base.
 4. A compound of claim1 which is N-[(2,3-dihydroxypropoxy)hydroxyphosphinyll-(S)Leu-(S)Trp-OH,its isomers as well as its addition salts with a pharmaceuticallyacceptable acid or base.
 5. A pharmaceutical composition useful as anendothelin convertase inhibitor comprising as active principle aneffective amount of a compound as claimed in claim 1, together with oneor more pharmaceutically-acceptable excipients or vehicles.